NM_031418.4:c.46+83G>T

Variant names:

• chr11-26332404-G-T
• rs17243259
• NM_031418.4:c.46+83G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031418.4(ANO3):​c.46+83G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,360,684 control chromosomes in the GnomAD database, including 64,044 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6019 hom., cov: 26)
  • Exomes 𝑓: 0.31 (58025 hom.)
• Consequence: ANO3 NM_031418.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.00
• Publications: 7 publications found

Genes affected

ANO3 (HGNC:14004): (anoctamin 3) The protein encoded by this gene belongs to the TMEM16 family of predicted membrane proteins, that are also known as anoctamins. While little is known about the function of this gene, mutations in this gene have been associated with some cases of autosomal dominant craniocervical dystonia. Cells from individuals with a mutation in this gene exhibited abnormalities in endoplasmic reticulum-dependent calcium signaling. Studies in rat show that the rat ortholog of this protein interacts with, and modulates the activity of a sodium-activated potassium channel. Deletion of this gene caused increased pain sensitivity in the rat model system. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

ANO3 Gene-Disease associations (from GenCC):

• dystonia 24

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-26332404-G-T is Benign according to our data. Variant chr11-26332404-G-T is described in ClinVar as Benign. ClinVar VariationId is 1249245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031418.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO3	NM_031418.4	MANE Select	c.46+83G>T		intron	N/A	NP_113606.2	Q9BYT9-1
	ANO3	NM_001313726.2		c.229+22685G>T		intron	N/A	NP_001300655.1	A0A5F9ZHL6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO3	ENST00000256737.8	TSL:1 MANE Select	c.46+83G>T		intron	N/A	ENSP00000256737.3	Q9BYT9-1
	ANO3	ENST00000672621.1		c.229+22685G>T		intron	N/A	ENSP00000500506.1	A0A5F9ZHL6
	ANO3	ENST00000525139.5	TSL:5	c.-3+22685G>T		intron	N/A	ENSP00000432576.1	E9PQ79

Frequencies

GnomAD3 genomes AF: 0.280 AC: 41641 AN: 148684 Hom.: 6017 Cov.: 26

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.187

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.265

GnomAD4 exome AF: 0.307 AC: 371609 AN: 1211884 Hom.: 58025 AF XY: 0.308 AC XY: 189796 AN XY: 615272

African (AFR) AF: 0.227 AC: 6547 AN: 28832

American (AMR) AF: 0.263 AC: 11568 AN: 43902

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 5804 AN: 24428

East Asian (EAS) AF: 0.166 AC: 6374 AN: 38438

South Asian (SAS) AF: 0.344 AC: 27912 AN: 81076

European-Finnish (FIN) AF: 0.381 AC: 20240 AN: 53128

Middle Eastern (MID) AF: 0.300 AC: 1566 AN: 5220

European-Non Finnish (NFE) AF: 0.312 AC: 276187 AN: 884746

Other (OTH) AF: 0.296 AC: 15411 AN: 52114

GnomAD4 genome AF: 0.280 AC: 41673 AN: 148800 Hom.: 6019 Cov.: 26 AF XY: 0.281 AC XY: 20335 AN XY: 72250

African (AFR) AF: 0.230 AC: 9271 AN: 40322

American (AMR) AF: 0.244 AC: 3603 AN: 14794

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 818 AN: 3462

East Asian (EAS) AF: 0.169 AC: 851 AN: 5050

South Asian (SAS) AF: 0.328 AC: 1530 AN: 4662

European-Finnish (FIN) AF: 0.367 AC: 3587 AN: 9764

Middle Eastern (MID) AF: 0.281 AC: 82 AN: 292

European-Non Finnish (NFE) AF: 0.314 AC: 21217 AN: 67492

Other (OTH) AF: 0.265 AC: 544 AN: 2054

Alfa AF: 0.300 Hom.: 26914

Bravo AF: 0.272

Asia WGS AF: 0.268 AC: 930 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Dystonia 24 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.0
DANN	Benign	0.72
PhyloP100		-1.0
PromoterAI		0.030	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17243259; hg19: chr11-26353951; COSMIC: COSV56792030;